The primary goal of the Epi4K Center Without Walls Is to Increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The strategy used in this project (5 of 7 - Multiplex Families &Pairs) is to enrich the study sample for genetic influences on epilepsy by studying families containing multiple individuals. The families to be studied include 1500 pairs of affected first-degree relatives and 300 families containing three or more affected individuals previously collected and phenotyped in detail. We propose to define new familial epilepsy syndromes likely to have distinct genetic mechanisms, perform comprehensive analyses of genomic variation influencing risk for epilepsy, and assess the specificity of effect o identified risk-raising variants for specific clinically defined subsets. The project has four PIs ith skills, experience and track record in clinical epileptology, high level phenotyping, clinical and molecular genetics of epilepsy, genetic epidemiology and statistical genetics: Drs. Sam Berkovic of University of Melbourne (contact PI), Ruth Ottman of Columbia University, Michael Epstein of Emory University and Patrick Cossette of Centre Hospitaller de I'Universite de Montreal This comprehensive genomic analysis of a large sample enriched for genetic influences on epilepsy is likely to transform understanding of the pathways leading to this complex and heterogeneous disorder. PUBLIC HEALTH RELEVANCE: .Epilepsy is one of the most common neurologic disorders, affecting up to 4% of the population. Although inherited factors clearly influence risk for epileps, little is known about the specific genes Involved. The Epi4K project will Identify new genes and genetic pathways leading to epilepsy and will directly benefit individuals with epilepsy and their families through improved diagnosis, treatments, and cures. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.